Endometriosis is a chronic disease that affects nearly 5 million American women, or nearly 1 in 7 women of reproductive age (Klotz et al., 1995). Although endometriosis causes significant disability and distress in millions of women, it is often undiagnosed and, in general, is poorly understood (Corwin, 1997). Endometriosis is a benign disease that presents pleomorphic lesions of endometrial tissue containing glands or stroma or both growing at sites outside the uterine corpus. The ectopic sites include the ovaries, broad ligaments, rectovaginal septum, umbilicus, and laparotomy scars. The endometrial glands respond to hormonal stimuli, resulting in cyclic menstrual bleeding in the ectopic foci. Blood accumulates in cystic structures that are surrounded by inflammatory adhesions. Infertility, dysmenorrhea and chronic pelvic pain are the main symptoms, and are significant gynecological problems.
The exact etiology of this disease is controversial, but endometriosis occurs infrequently outside of the reproductive years, and appears to develop principally from the ectopic implantation of endometrial tissue entering the peritoneal space at the time of menstruation (Ishimaru et al., 1991; Sampson et al., 1927). Additionally, numerous experimental observations demonstrate that introduction of endometrial fragments into the peritoneal space of women (Ridley, 1968) and nonhuman primates (TeLinde et al., 1950) can result in the development of endometriosis.
Although retrograde menstruation has been reported in most women (Halme et al., 1984), endometriosis does not develop in all of them. Accumulating evidence suggests that altered cellular immunity may be involved in the pathogenesis of endometriosis both in women and in rhesus monkeys (Steele et al., 1984; Oosterlynck et al., 1991). Decreased in vitro lymphocyte proliferation in response to autologous endometrial cells has been reported in both rhesus monkeys and women with endometriosis (Steele et al., 1984). Decreased autologous antiendometrial lymphocytotoxicity and decreased natural killer (NK) cell activity has been reported in women with endometriosis when compared with women with a normal pelvis by some but not by other investigators (D'Hooghe et al., 1996).
There is evidence that immune surveillance is altered in women with endometriosis (Steele et al., 1984; Oosterlynck et al., 1991), which may facilitate the implantation of retrogradely shed menstrual endometrial cells. Whether immunosuppression facilitates the development of endometriosis is unknown. Immunosuppression has known profound effects on cellular and humoral immunity: global defects of T- and B-cell populations; decreased NK cell activity; 50% suppression of phytohemagglutinin-, concanavalin A-, and pokeweed mitogen-stimulated blastogenesis; decreased T-helper-T-suppressor ratio; impaired T-suppressor cell function; and reduced in vitro lymphokine-activated NK cell activity (D'Hooghe et al., 1996).
NK cell activity is decreased in women with endometriosis (Oosterlynck et al., 1991; Vigano et al., 1991). The reduced activity is not the result of a quantitative defect in these cells, nor does it appear to cause a significant reduction in systemic immunity (Oosterlynck et al., 1991; Vigano et al., 1991). The reduced NK cell activity may then result in a deficiency in the ability to reject autologous endometrial tissue, causing these women to have an increased risk for the development of endometriosis (Oosterlynck et al., 1991; Vigano et al., 1991).
Because of the expense and difficulties of human and primate research, models for the study of endometriosis have been developed in several other mammals. Many attempts have been made to elucidate the pathogenesis of endometriosis and to evaluate the therapeutic ability of new drugs against endometriosis by autotransplantation of endometrium to the peritoneal cavity of the subcutaneous layer in various laboratory animals, including rats (Klotz et al., 1995; Corwin, 1997; Ishimura et al., 1991), rabbits (Sampson, 1927; Ridley, 1968), monkeys (TeLinde et al., 1950; Halme et al., 1984) and mice (Aoki et al., 1994). The surgical transplantation of endometrial tissue wedges into the peritoneal sidewall and/or onto the ovary is the typical animal model used for studying endometriosis (Aoki et al., 1994; Vernon et al., 185; Zamah et al., 1984). This type of research model is helpful in investigating the effects of medications on ectopic endometrial tissue growth as well as in the in vivo pathophysiologic actions of these implants (Ramey et al., 1996).
The various existing animal models of endometriosis include the mouse (Yang and Foster, 1997), and the rat (Vernon and Wilson, 1985; Yang et al, 1996), where endometriosis is surgically induced by excising the uterine horn and uterine explants in ovariectomized rats and placed in anterior and posterior bifurcation of the uterine horns, and estrogen capsules implanted under the skin or exogenous hormone treatments. However, a major hurdle for understanding the etiology, pathophysiology and spontaneous evolution of the disease is the lack of an appropriate animal model closely mimicking human endometriosis.
Thus, what is needed is a non-human animal model for endometriosis.